Search

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic diabetes characterized by onset at a young age and an autosomal dominant mode of inheritance. Notably, MODY accounts for 2%-5% of all diabetes cases, and its distinction from types 1 (T1DM) and 2 (T2DM) diabetes mellitus is often challenging. We report herein the cases of two girls and a boy who presented initially with diabetic ketoacidosis. In view of the strong family history of diabetes in all three of them, the diagnosis of MODY was considered and confirmed by molecular testing. The patient in Case 1 (a 10-year-old girl) had a variation in the HNF1A gene (MODY 3). The patient in Case 2 (a 13-year-old girl) had a variation in the HNF1B gene (MODY 5) and was also clinically diagnosed with HNF1B MODY due to short stature, abnormal renal function, renal cysts, unicornuate uterus, and diabetic ketoacidosis at presentation. The patient in Case 3 (a 14-year-old boy) had a variation in the KCNJ11 gene (MODY 13) and presented with diabetic ketoacidosis; after initially being treated as having T1DM, he developed progressive weight gain, acanthosis nigricans, and decreased requirement of insulin. The patients in Cases 1 and 3 were subsequently treated with oral sulfonylureas and insulin was gradually tapered and interrupted, resulting in drastic improvement in glucose control. The patient in Case 2 remained on insulin, as this is the appropriate management for MODY 5. This case series demonstrates that atypical cases of MODY with ketoacidosis do occur, underscoring the potential for this complication within the phenotypic spectrum of MODY. In patients with atypical presentations, a thorough family history taking may reveal the diagnosis of MODY., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.

The MNX1 gene encodes a homeobox transcription factor found to be important for pancreatic beta cell differentiation and development. Mutations of the MNX1 gene that cause permanent neonatal diabetes mellitus (PNDM) are rare and have been reported in only two cases. Both cases presented with hyperglycemia, with one case having isolated PNDM while the other had PNDM and multiple neurologic, skeletal, lung, and urologic congenital anomalies resulting in death in early infancy. We describe the genetic and clinical features of a preterm male infant with a homozygous [c.816C > A p.(Phe272Leu)] MNX1 mutation. Our proband is the first case to present in severe diabetic ketoacidosis (DKA), indicating severe insulin deficiency. Unlike the previously reported female case who had the same mutation and presented with isolated PNDM, our proband had hypospadias and congenital umbilical hernia and showed poor growth on follow up. Our case suggests that MNX1 mutations causing NDM can result in a range of extra-pancreatic features and a variable phenotype, similar to other transcription factors causing NDM such as GATA6 and GATA4 mutations. We also cannot exclude the possibility of sex-biased expression of MNX1 gene (which was recently reported for other monogenic/neonatal diabetes genes such as the NEUROD1 and HNF4A in humans) since the two male cases had associated multiple anomalies while the female case had isolated PNDM. Our report further defines the phenotype caused by recessive homozygous MNX1 mutations and explores potential new mechanisms regulating MNX1 gene expression which should be further explored., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: To investigate the potential causal relationship between non-alcoholic fatty liver disease (NAFLD) and complications in type 1 diabetes (T1D) and type 2 diabetes (T2D)., Materials and Methods: Two-sample Mendelian randomization (MR) analysis was conducted to appraise after controlling for the confounding factors. Genetic instrument variables for NAFLD surrogated by chronically elevated serum alanine transferase were derived from a recent genome-wide association study. Diabetes-related complications, including diabetic ketoacidosis, nephropathy and retinopathy, were included as outcomes. Four complementary MR methods were used to test reliability., Results: Genetically instrumented NAFLD showed a suggestive causal association with ketoacidosis in T1D (odds ratio [OR]: 1.574; 95% confidence interval [CI]: 1.076, 2.302; P = .019; false discovery rate [FDR] = 0.096) and a significant causal association with early-stage kidney disease in T1D (OR: 1.249; 95% CI: 1.089, 1.432; P = 1.457 × 10 -3 , FDR = 0.015). Sensitivity analysis indicated low heterogeneity, low pleiotropy and high reliability of the causal estimates. However, the MR analyses failed to show a causal association between NAFLD and T1D retinopathy, T2D ketoacidosis, nephropathy and retinopathy., Conclusions: This study supports a causal effect of genetically driven chronic serum alanine aminotransferase-associated NAFLD on early-stage kidney disease in T1D and a suggestive causal effect on ketoacidosis in T1D. However, MR studies did not provide enough evidence to suggest that NAFLD independently increases the risk of retinopathy in T1D and of ketoacidosis, nephropathy and retinopathy in T2D., (© 2022 John Wiley & Sons Ltd.)

A 16-year-old child with no medical history was admitted to the hospital emergency for abdominal pain associated with polyuria-polydipsia and weight loss (baseline BMI: 25,4 kg/m2). Diagnosis of severe ketoacidosis was quickly raised regarding major metabolic acidosis, high ketonemia and glycemia. Acute pancreatitis was then diagnosed according to a plasmatic lipase more than tenfold normal values associated with a severe hypertriglyceridemia superior to 100 mmol/L. The triad composed of diabetic ketoacidosis-acute pancreatitis-hypertriglyceridemia is rarely found in childhood and can have deleterious consequences. The etiology of this disease is still enigmatic, as one can be both, cause and consequence of the other. Genetic investigation of familial chylomicronemia legitimated to invalidate the dyslipidemia etiology of this event. On the other hand, the association of a genetic variant of lipoprotein lipase leading to a decrease in its activity, with the insulinopenia of type 1 diabetes most certainly triggered this episode of hypertriglyceridemia.

Pathogenic INS gene mutations are causative for mutant INS-gene-induced diabetes of youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Alterations in natural killer (NK) cells activity cause damage to pancreatic islets in type 1 diabetes mellitus (T1DM). The aim of this study is to identify T1DM ketosis- or ketoacidosis-related genes in activated CD56 + CD16 + NK cells., Methods: Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Enrichment analyses were performed using Metascape online database and GSEA software. Cell-specific gene co-expression network was built using NetworkAnalyst tools. Cytoscape software was used to identify hub genes and construct co-expressed networks. Target miRNAs were predicted based on the DIANA-micro T, miRDB, and miRWalk online databases., Results: A total of 70 DEGs were identified between T1DM patients recovered from ketosis or ketoacidosis and healthy control blood samples in GSE44314. Among the DEGs, 10 hub genes were screened out. The mature NK cell-specific gene co-expression network for DEGs in T1DM was built using NetworkAnalyst tools. DEGs between activated CD56 + CD16 + NK cells and CD56 bright CD16 - NK cells were identified from GSE1511. After intersection, 13 overlapping genes between GSE44314 and GSE1511 microarray datasets were screened out, in which 7 hub genes were identified. Additionally, 59 target miRNAs were predicted according to the 7 hub genes. After validating with the exosome miRNA expression profile dataset of GSE97123, seven differentially expressed miRNAs (DEmiRNAs) in plasma-derived exosome were selected. Finally, a mRNA-miRNA network was constructed, which was involved in the T1DM ketosis or ketoacidosis process., Conclusion: This work identified seven hub genes in activated CD56 + CD16 + NK cells and seven miRNAs in plasma-derived exosome as potential predictors of T1DM ketoacidosis, which provided a novel insight for the pathogenesis at the transcriptome level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shi, Dai, He, Sun, Xu, Deng and Zhang.)

Objective: To further understand clinical and biochemical features, and HLA-DRB1 genotypes, in new cases of diabetes in Sudanese children and adolescents., Research Design and Methods: Demographic characteristics, clinical information, and biochemical parameters (blood glucose, HbA1c, C-peptide, autoantibodies against glutamic acid decarboxylase 65 [GADA] and insulinoma-associated protein-2 [IA-2A], and HLA-DRB1) were assessed in 99 individuals <18 years, recently (<18 months) clinically diagnosed with T1D. HLA-DRB1 genotypes for 56 of these Arab individuals with T1D were compared to a mixed control group of 198 healthy Arab (75%) and African (25%) individuals without T1D., Results: Mean ± SD age at diagnosis was 10.1 ± 4.3 years (range 0.7-17.6 years) with mode at 9-12 years. A female preponderance was observed. Fifty-two individuals (55.3%) presented in diabetic ketoacidosis (DKA). Mean ± SD serum fasting C-peptide values were 0.22 ± 0.25 nmol/L (0.66±0.74 ng/ml). 31.3% were autoantibody negative, 53.4% were GADA positive, 27.2% were IA-2A positive, with 12.1% positive for both autoantibodies. Association analysis compared to 198 controls of similar ethnic origin revealed strong locus association with HLA-DRB1 (p < 2.4 × 10 -14 ). Five HLA-DRB1 alleles exhibited significant T1D association: three alleles (DRB1*03:01, DRB1*04:02, and DRB1*04:05) were positively associated, while three (DRB1*10:01, DRB1*15:02, and DRB1*15:03) were protective. DRB1*03:01 had the strongest association (odds ratio = 5.04, p = 1.7 × 10 -10 )., Conclusions: Young Sudanese individuals with T1D generally have similar characteristics to reported European-origin T1D populations. However, they have higher rates of DKA and slightly lower autoantibody rates than reported European-origin populations, and a particularly strong association with HLA-DRB1*03:01., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA's metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6-12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA's acute and chronic insults., Competing Interests: The authors have declared that no competing interests exist.

Background: This study aimed to analyze the genetics and treatments of the patients with the triad of diabetic ketoacidosis (DKA), hypertriglyceridemia, and acute pancreatitis (AP)., Methods: We conducted a retrospective study of six patients with the triad of AP, hypertriglyceridemia, and DKA at our hospital. All patients underwent plasmapheresis as part of their treatment. The clinical characteristics of the patients were obtained from the hospital information system and analyzed. Whole exome sequencing was performed using samples of one patient (case 6) and his family members., Results: The average triglyceride level before plasmapheresis was 3282.17 ± 2975.43 mg/dL (range: 1646-9332 mg/dL). The triglyceride levels dropped by approximately 80% after plasmapheresis. None of the patients developed complications related from plasmapheresis. During follow-up, patients 5 and 6 developed recurrent pancreatitis for several times and showed the formation of pancreatic pseudocysts. We identified three novel heterozygous missense mutations in the family of patient 6, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD., Conclusions: Three novel heterozygous missense mutations, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD were first identified in a patient with the triad of DKA, hypertriglyceridemia, and AP. The combination of plasmapheresis, hydration, and insulin therapy may have the greatest clinical benefits for these patients., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aims/hypothesis: The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents., Methods: An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status., Results: During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0 years [5.5-11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia., Conclusions/interpretation: DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups.

Objective: Diabetic ketoacidosis is one of the most serious acute complications of the gestational diabetes and is marked by the triad of the uncontrolled hyperglycemia, acidosis, and ketosis. Diabetic ketoacidosis can be a life-threatening emergency for mother and fetus, whose genetic factors resulting in diabetic ketoacidosis remain unclear. This study aimed to explore the correlation between SLC26A6 gene polymorphism rs184187143 and the risk of diabetic ketoacidosis of gestational diabetic mellitus (GDM)., Patients and Methods: A total of 98 patients with GDM and 98 patients with diabetic ketoacidosis of GDM were enrolled. The direct sequencing of the products by Polymerase Chain Reactions of the extracted genomic DNA from the involved patients was performed to analyze the SLC26A6 gene polymorphism rs184187143, and the further genotype frequencies were compared to the statistical analysis of the clinical and biochemical data., Results: A significantly increased prevalence of the G allele (p = 0.032, OR = 2.326, 95% CI = 1.539-3.516), C/G genotype (p = 0.021, OR = 3.582, 95% CI = 1.216-10.558), and a previously uncharacterized rs184187143, was discovered in the diabetic ketoacidosis of the GDM group. The genotype of SLC26A6 rs184187143 was shown to be markedly associated with increased prevalence of the diabetic ketoacidosis of GDM., Conclusions: Our study firstly established that the G allele and C/G genotype of rs184187143 single nucleotide polymorphism (SNP) in SLC26A6 gene was closely linked with the increased risk for the development of the diabetic ketoacidosis of GDM.

Neonatal diabetes mellitus (NDM) is a rare condition that presents with diabetes in the first few months of life. The treatment of NDM may differ depending on the genetic etiology, with numerous studies showing the benefit of sulfonylurea therapy in cases caused by mutations in KCNJ11 or ABCC8 Mutations in the insulin gene ( INS ) have also been identified as causes of NDM; these cases are generally best treated with insulin alone. We report a case of a female infant born small for gestational age (SGA) at late preterm diagnosed with NDM at 7 wk of life who was found by rapid whole-genome sequencing to harbor a novel de novo c.26C>G (p.Pro9Arg) variant in the INS gene. She presented with diabetic ketoacidosis, which responded to insulin therapy. She did not respond to empiric trial of sulfonylurea therapy early in her hospital course, and it was discontinued once a genetic diagnosis was made. Early genetic evaluation in patients presenting with NDM is essential to optimize therapeutic decision-making., (© 2019 Laurenzano et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes (T1D). Little is known about the association between genetic and immunological markers and the risk for DKA at onset of T1D. The aim of this study was to create a model foreseeing the onset of DKA in newly diagnosed patients., Methods: This retrospective study included 532 T1D children (aged <18 years at diagnosis) recruited in our hospital, from 1995 to 2014. DKA and its severity were defined according to the criteria of ISPAD. Genetic risk categories for developing T1D were defined according to the Belgian Diabetes Registry. Multivariate statistical analyses were applied to investigate risk factors related to DKA at diagnosis., Results: Overall 42% of patients presented DKA at diagnosis. This study outlined the major risk of DKA at diagnosis for younger children (<3 years) and for those belonging to ethnic minorities. Children carrying neutral genotypes had a 1.5-fold increased risk of DKA at diagnosis than those with susceptible or protective genotypes, a paradoxical observation not previously reported. Only solitary positive IA-2A increased the risk of DKA at diagnosis. The proposed model could help to predict the probability of DKA in 70% of newly diagnosed cases., Conclusions: This was the first reported implication of IA-2A positivity and neutral genotypes predisposing to DKA at diagnosis regardless of its severity. Earlier diagnosis through genetic and immunological screening of high-risk children could decrease DKA incidence at diabetes onset., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children's deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient's CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient's genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A+β+ ketosis prone diabetes (KPD) is associated with slowly progressive autoimmune beta cell destruction. Plasma unmethylated and methylated insulin DNA (biomarkers of ongoing beta cell damage and systemic inflammation, respectively) were elevated in A+β+ KPD compared to all other KPD subgroups., (Copyright © 2017. Published by Elsevier Inc.)

Neonatal diabetes mellitus is a rare monogenic disease with incidence of 1/90,000 newborns. A case of two months aged male infant with life threatening diabetic ketoacidosis is presented with novel ABCC8 gene mutation (p.F577L), successful transition from insulin to sulfonylurea and follow-up of three years., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To study the genetic mutations and clinical profile in children with neonatal diabetes mellitus., Methods: Genetic evaluation, clinical management and follow-up of infants with neonatal diabetes., Results: Eleven infants were studied of which eight had permanent neonatal diabetes. Median age at presentation was 8 weeks and mean (SD) birth weight was 2.4 (0.5) kg. Pathogenic genetic mutations were identified in 7 (63.6%) children; 3 infants with mutations in KCNJ11 gene and 1 in ABCC8 were switched to oral sulfonylureas; 2 infants had mutations in INS and 1 in ZFP57., Conclusion: Neonatal diabetes mellitus is a heterogeneous disorder. Identification of genetic cause guides clinical management.

Due to the limited data on diabetic ketoacidosis and brain edema (DKA/BE) in children/adolescents and the lack of recent data on adults with type 1 diabetes (T1D), we addressed the question of whether neuroinflammation was present in the fatal DKA of adults. We performed immunohistochemistry (IHC) studies on the brains of two young adults with T1D and fatal DKA and compared them with two teenagers with poorly controlled diabetes and fatal DKA. C5b-9, the membrane attack complex (MAC) had significantly greater deposits in the grey and white matter of the teenagers than the young adults (p=0.03). CD59, a MAC assembly inhibitory protein was absent, possibly suppressed by the hyperglycemia in the teenagers but was expressed in the young adults despite comparable average levels of hyperglycemia. The receptor for advanced glycation end products (RAGE) had an average expression in the young adults significantly greater than in the teenagers (p=0.02). The autophagy marker Light Chain 3 (LC3) A/B was the predominant form of programmed cell death (PCD) in the teenage brains. The young adults had high expressions of both LC3A/B and TUNEL, an apoptotic cell marker for DNA fragmentation. BE was present in the newly diagnosed young adult with hyperglycemic hyperosmolar DKA and also in the two teenagers. Our data indicate that significant differences in neuroinflammatory components, initiated by the dysregulation of DKA and interrelated metabolic and immunologic milieu, are likely present in the brains of fatal DKA of teenagers when compared with young adults., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Type 2 diabetes is thought to involve a compromised β cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult β cell identity and function. PAX6 was downregulated in β cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in β cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of β cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of β cell genes, thus maintaining mature β cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human β cells. We conclude that reduced expression of PAX6 in metabolically stressed β cells may contribute to β cell failure and α cell dysfunction in diabetes., Competing Interests: The authors have declared that no conflict of interest exists.

Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Severe hypertriglyceridemia is a condition associated with extremely high triglycerides (TG) plasma concentrations exceeding 1000mg/dl. This condition may result in mutations in genes encoding lipoprotein lipase (LPL), apolipoprotein C2 (APOC2) and apolipoprotein A5 (APOA5) characterized by an autosomal recessive inheritance pattern., Aim: A case report of a patient in which clinical picture of type 1 diabetes mellitus (T1DM) was accompanied by diabetic ketoacidosis (DKA) and severe hypertriglyceridemia., Case Report: A 2.5-year-old boy was admitted to the hospital with ketoacidosis (pH - 7.0, BE - 20mmol/l, HCO3 10mmol/l), glucose level of 850mg%, hyponatremia (Na 100mmol/l) and hyperlipidemia (TG 13493 mg/dl, TC 734 mg/dl). The administered treatment resulted in nearly normal glycemic values and lipid disturbances normalization. This child was diagnosed with a heterozygous mutation of the LPL gene. Currently with an intensive insulin therapy and correct metabolic control of type 1 diabetes mellitus (T1DM), this patient maintains a normal lipid profile., Conclusion: In patient with T1DM the diagnosis of severe hypertriglyceridemia in the course of ketoacidosis should be based on careful interpretation of laboratory tests results. Moreover genetic tests of the patient and his/her immediate relatives blood samples should be performed., (© Polish Society for Pediatric Endocrinology and Diabetology.)

Diabetes mellitus is a metabolic disease characterised by chronically high glucose levels. Genetic factors have been implicated in the aetiology following mutations in a single gene. An extremely rare form of diabetes mellitus is monogenic diabetes, a subset of which is permanent neonatal diabetes, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. We present the first case reported from East Africa of a child diagnosed with permanent neonatal diabetes resulting from a mutation in the KCNJ11 gene encoding the Kir6.2 subunit. Despite the rarity of permanent neonatal diabetes, this diagnosis should be considered in infants with persistent hyperglycaemia requiring insulin therapy. Children with an ATP-sensitive potassium channel defect in the pancreatic beta cell have an overall good prognosis when treated with oral sulphonylurea therapy.

Cerebral infarction is one of the serious neurological complications of diabetic ketoacidosis (DKA). Especially in patients who are genetically prone to thrombosis, cerebral infarction may develop due to inflammation, dehydration, and hyperviscocity secondary to DKA. A 6-year-old child with DKA is diagnosed with cerebral infarction after respiratory insufficiency, convulsion, and altered level of consciousness. Femoral and external iliac venous thrombosis also developed in a few hours after central femoral catheter had been inserted. Heterozygous type of factor V Leiden and PAI-14G/5G mutation were detected. In patients with DKA, cerebral infarction may be suspected other than cerebral edema when altered level of consciousness, convulsion, and respiratory insufficiency develop and once cerebral infarction occurs the patients should also be evaluated for factor V Leiden and PAI-14G/5G mutation analysis in addition to the other prothrombotic risk factors.

Background/aims: Activating mutations in the ABCC8 gene encoding the KATP channel subunit SUR1 cause β-cell dysfunction with non-autoimmune diabetes mellitus in neonates or infants. We investigated whether activating ABCC8 mutations affect endocrine pancreas development., Methods: We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus. He died of ketoacidosis. Postmortem pancreas specimens were evaluated by fluorescent microscopy after immunostaining for insulin, glucagon, somatostatin, and PCNA, and Hoechst 33342 nuclear staining. We compared the findings to those in 5 age-matched controls., Results: The number of islets was decreased and the number of single or small clusters of insulin cells increased in the patient compared to the age-matched controls. The islets in the patient had an insulin-cell core surrounded by intermingled glucagon and somatostatin cells. The insulin/Hoechst surface ratio was decreased and the glucagon/Hoechst surface ratio increased in the patient (4.3 and 8.8%, respectively) versus the controls (8.2 and 3.1%, respectively). Somatostatin surface staining was similar in the patient and controls (4 vs. 4.7%). PCNA staining was increased 3- to 3.5-fold, indicating increased insulin-cell proliferation compared to controls., Conclusion: Activating ABCC8 mutations impaired the balance between β and α cells in the patient, suggesting an effect on β-cell mass development.

Objective: Ketosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative ("A-") phenotypic forms: "A-β-" (lean, early onset, lacking β-cell functional reserve) and "A-β+" (obese, late onset, with substantial β-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A-β+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant ("provoked," with progressive β-cell function loss over time) or no precipitant ("unprovoked," with sustained β-cell functional reserve). These three A- KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown., Research Design and Methods: Islet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A-β- (n = 7), provoked A-β+ (n = 15), and unprovoked A-β+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes-associated HLA class II alleles., Results: Provoked A-β+ and A-β- KPD patients manifested stronger islet-specific T-cell responses (P < 0.03) and higher percentages of proinflammatory CD14+CD16+ monocytes (P < 0.01) than unprovoked A-β+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed., Conclusions: Provoked A-β+ KPD and A-β- KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A-β+ KPD lacks both humoral and cellular islet autoimmunity.

A 21-year-old man with diabetic ketoacidosis (DKA) displayed short and clubbed fingers and marked eyebrow, which are typical of Hajdu-Cheney Syndrome (HCS). Laboratory findings confirmed type 1 diabetes mellitus (DM). After conservative care with hydration and insulin supply, metabolic impairment was improved. Examinations of bone and metabolism revealed osteoporosis and craniofacial abnormalities. The mutation (c.6443T>G) of the NOTCH2 gene was found. The patient was diagnosed with HCS and DM. There may be a relationship between HCS and DM, with development of pancreatic symptoms related to the NOTCH2 gene mutation.

A 59-year-old Chinese male patient was admitted at diagnosis of type 1 diabetes with ketoacidosis. During the normalization of blood glucose with insulin, the patient developed acute hemolysis. The factors predisposing to hemolysis were not found, except the significantly diminished activity of glucose-6-phosphate dehydrogenase (G6PD). DNA analysis did not show any coding or intronic mutation in the G6PD gene. This is the first reported case of a Chinese patient in diabetic ketoacidosis with hemolysis induced by G6PD deficiency in the absence of mutations in the G6PD gene.

Objective: To explore the relationship between family history of diabetes and frequency of diabetic ketoacidosis (DKA) at diagnosis and to analyze the possible association between HLA genotypes and DKA., Design and Methods: We recruited 510 children and adolescents aged <17 years with type 1 diabetes (T1D) and collected information on first-degree relative (FDR) history of T1D. DKA and severe DKA were defined as blood pH <7.30 and <7.10 at diabetes onset respectively. Risk categories for developing T1D were determined according to various HLA DQA1-DQB1 haplotype combination genotypes., Results: The frequency of DKA and severe DKA at diagnosis was 34.7 and 7.2% respectively. DKA was more frequent in younger patients (<2 years (60.0%; P<0.001)) and occurred less in children with at least one FDR affected by T1D (13.0 vs 37.4%, P<0.001). The logistic regression showed that age at diagnosis (<2 years) and increased HLA-associated risk genotypes were independent predictors of DKA (P<0.01, odds ratio (OR)=1.068 (95% confidence interval (CI) 1.021-1.117); P<0.05, OR=1.606 (95% CI 1.034-2.475)). Introducing the presence of T1D in at least one FDR in the logistic model, a significant association between DKA and age at diagnosis (<2 years; P<0.01, OR=1.072 (95% CI 1.024-1.123)) and absence of FDRs with T1D (P=0.001, OR=4.287 (95% CI 1.770-10.383)) was found, but no more with increased HLA-associated risk genotype (P=0.06, OR=1.550 (95% CI 0.992-2.423))., Conclusions: HLA-associated high-risk genotypes are associated with a high chance of presenting DKA at diabetes onset. However, having at least one FDR with T1D reduced the risk of DKA regardless of HLA genotype.

McCune-Albright syndrome (MAS) consists of the triad of polyostotic fibrous dysplasia, cutaneous pigmentation, and multiple endocrine abnormalities. Type 1 diabetes mellitus is not included in MAS. We report the case of an 18-year-old girl who presented with McCune-Albright syndrome. The diagnosis was made by the presence of precocious puberty at the age of 6 years, cutaneous pigmentation, polyostotic fibrous dysplasia, and phosphate diabetes. Type 1 diabetes mellitus developed at the age of 16 years. We discuss this case, the relationship between type 1 diabetes mellitus and MAS, with a literature review., (Copyright © 2012. Published by Elsevier SAS.)

KATP channels regulate insulin secretion by coupling β-cell metabolism to membrane excitability. These channels are comprised of a pore-forming Kir6.2 tetramer which is enveloped by four regulatory SUR1 subunits. ATP acts on Kir6.2 to stabilize the channel closed state while ADP (coordinated with Mg(2+)) activates channels via the SUR1 domains. Aberrations in nucleotide-binding or in coupling binding to gating can lead to hyperinsulinism or diabetes. Here, we report a case of diabetes in a 7-mo old child with compound heterozygous mutations in ABCC8 (SUR1[A30V] and SUR1[G296R]). In unison, these mutations lead to a gain of KATP channel function, which will attenuate the β-cell response to increased metabolism and will thereby decrease insulin secretion. (86)Rb(+) flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of (86)Rb(+) efflux relative to WT channels. Experiments on excised inside-out patches also reveal a slight increase in activity, manifested as an enhancement in stimulation by MgADP in channels expressing the compound heterozygous mutations or homozygous G296R mutation. In addition, the IC 50 for ATP inhibition of homomeric A30V channels was increased ~6-fold, and was increased ~3-fold for both heteromeric A30V+WT channels or compound heterozygous (A30V +G296R) channels. Thus, each mutation makes a mechanistically distinct contribution to the channel gain-of-function that results in neonatal diabetes, and which we predict may contribute to diabetes in related carrier individuals.

Objective: Our purpose was to assess whether family history of diabetes or the HLA-DR-DQ genotype of the index case was associated with the frequency of diabetic ketoacidosis (DKA) at diagnosis of childhood type 1 diabetes., Patients and Methods: The study cohort comprised 1518 children aged <15 years and diagnosed with type 1 diabetes in Finland in 2002-2005. Family history of type 1 and type 2 diabetes among first-degree relatives (FDRs) and grandparents was assessed at diagnosis. HLA-DR-DQ genotypes were analysed using time-resolved fluorometry., Results: In total, 12.6 and 1.7% of children had at least one FDR affected with type 1 or type 2 diabetes, respectively, and 6.6 and 34.8% had at least one grandparent with type 1 or type 2 diabetes. DKA (pH <7.30) occurred less frequently in children having a type 1 diabetes affected FDR (7.4 vs 20.5%, P<0.001). Type 2 diabetes among the parents or grandparents had no such effect. Lower risk HLA genotypes were observed to predispose to DKA (P<0.024). In a logistic regression analysis, the risk of DKA was independently associated with the absence of a family member affected by type 1 diabetes, the presence of a low-risk HLA genotype and older age at diagnosis (odds ratio 3.23, 1.45 and 1.07 respectively)., Conclusion: The presence of type 1 diabetes in an FDR is associated with an decreased risk of DKA at diagnosis. The rate of DKA seems to be higher in children with lower HLA-conferred risk for type 1 diabetes.

Background: Neonatal diabetes mellitus (NDM) due to KCNJ11 gene mutation presents with diabetes in the first 3 months of life and sometimes with neurological features like developmental delay, muscle weakness and epilepsy., Methods: A 5-week-old boy presented with diabetic ketoacidosis. Molecular genetic analysis of the patient revealed heterozygous missense mutation, L233F in the KCNJ11 gene, while his mother was mosaic for the same mutation., Results: The treatment strategy was changed from insulin injections to oral glibenclamide and with a better glycemic control., Conclusion: The patient with NDM due to mutation L233F (not reported till date) in the KCNJ11 gene can be successfully treated with oral glibenclamide therapy.

Background: The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes., Methods: The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset., Results: A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03)., Conclusions: The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

Background: fulminant type 1 diabetes mellitus (T1DM) is characterized by abrupt onset of hyperglycemia and rapid progression to ketoacidosis. This study aimed at examining the clinical and autoimmunity features of fulminant T1DM in Chinese., Methods: a total of 24 patients with fulminant T1DM and 48 classical autoimmune T1DM patients with acute onset of ketoacidosis were recruited. Anthropometric and biochemical parameters were tested. Serum antibodies against glutamic acid decarboxylase 65, tyrosine phosphatase-2 and zinc transporter 8 were measured, and human leukocyte antigen-DQ haplotypes were determined. Peripheral glutamic acid decarboxylase 65-specific T-cell responses in some subjects were determined., Results: compared with autoimmune T1DM patients, patients with fulminant T1DM displayed more flu-like and gastrointestinal symptoms, and had significantly higher concentrations of plasma glucose, more severe ketoacidosis, very low levels of pancreatic β-cell reserve, but only slightly increased haemoglobin A(1c) levels. In some patients, the disease onset was associated with drug-related hypersensitivity, pregnancy, or positive serum IgM against viruses. Forty percent (8/20) had low titres of autoantibodies against at least one of the islet autoantigens tested. Three out of six patients had positive glutamic acid decarboxylase-reactive Th1 responses. The frequency of human leukocyte antigen -DQA1*0102-DQB1*0601 haplotype was significantly higher in patients with fulminant T1DM., Conclusions: fulminant T1DM is a distinct entity with unique clinical characteristics and may be mediated by multiple factors, including viral infection, pregnancy, and drug sensitivity syndrome, among others, in the presence of humoral and/or cellular autoimmunity and susceptible genetic background., (2010 John Wiley & Sons, Ltd.)

We aimed to characterize the different subgroups of ketosis-prone diabetes (KPD) in a sample of Tunisian patients using the Aβ scheme based on the presence or absence of β-cell autoantibodies (A+ or A-) and β-cell functional reserve (β+ or β-) and we investigated whether HLA class II alleles could contribute to distinct KPD phenotypes. We enrolled 43 adult patients with a first episode of ketosis. For all patients we evaluated clinical parameters, β-cell autoimmunity, β-cell function and HLA class II alleles. Frequency distribution of the 4 subgroups was 23.3% A+β-, 23.3% A-β-, 11.6% A+β+ and 41.9% A-β+. Patients from the group A+β- were significantly younger than those from the group A-β- (P = .002). HLA susceptibility markers were significantly more frequent in patients with autoantibodies (P = .003). These patients also had resistance alleles but they were more frequent in A+β+ than A+β- patients (P = .04). Insulin requirement was not associated to the presence or the absence of HLA susceptibility markers. HLA class II alleles associated with susceptibility to autoimmune diabetes have not allowed us to further define Tunisian KPD groups. However, high prevalence of HLA resistance alleles in our patients may reflect a particular genetic background of Tunisian KPD population.

Objective: To investigate PAX4 gene polymorphism and its association with islet autoantibody-negative patients with ketosis-prone diabetes in Chinese Han population., Methods: We screened the variation of exon 3 and 9 within PAX4 gene by denaturing high performance liquid chromatography(DHPLC) in 112 non-diabetes control subjects (NC group) and 141 patients with ketosis-prone diabetes (KPD group), who were both negative for glutamic acid decarboxylase antibody (GAD-Ab) as well as protein tyrosine phosphatase antibody (IA-2Ab). The sequences of abnormal peaks were analyzed by DNA-sequencing. The A1168C single nucleotide polymorphism in PAX4 gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 308 non-diabetic control subjects and 141 KPD patients., Results: No variation was discovered in PAX4 gene exon 3 both in the patients and in the controls. There was a single nucleotide polymorphism locus A1168C in the PAX4 gene exon 9, which induced missence mutation P321H (rs712701). No significant difference was observed in the genotype and allele frequencies of A1168C polymorphism between KPD patients and control subjects (P=0.532, 0.426). The difference was detected in the CC genotype and C allele frequencies in the KPD group when patients were stratified by gender (P=0.009,0.028). According to age at diagnosis, the difference was observed in the CC genotype and C allele frequencies between <20 years old and > or = 20 years old in the KPD group (P=0.034,0.032). The level of FCP in the CC genotype group was significantly higher than that of FCP in AA genotype group (P=0.005)., Conclusion: A1168C polymorphism in PAX4 gene may not play an essential role in the genetic susceptibility of the islet autoantibody-negative KPD in Chinese Han population. However, A1168C variation may contribute to the predisposition to the male or < 20 years old patients with islet autoantibody-negative KPD.

Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder characterized by megaloblastic anemia, diabetes mellitus and progressive sensorineural deafness. We report the cases of two infants, aged 4 and 5 months, hospitalized for diabetic ketoacidosis requiring insulin therapy. Laboratory tests revealed megaloblasic anemia, thrombocytopenia and normal thiamine level. Neurosensorial investigations showed bilateral deafness and ophthalmic involvement. Treatment with oral thiamine normalized hematological disorders and controlled diabetes; however, thiamine therapy had no impact on neurosensorial disorders.

A one month old baby was admitted for diabetic keto-acidosis. There was no neurological or dysmorphic features. On genetic analysis a heterozygous missense mutation of ABCC8 gene which codes for SUR1 was detected. His insulin requirement progressively came down and by 6 months insulin was stopped and child now maintains normoglycaemia. Activating mutation in sulphonylurea receptor SUR1 is a very rare but described cause of neonatal diabetes mellitus.

We report a 2 month male child presenting with diabetic ketoacidosis (DKA) and seizures treated with intravenous fluids and intravenous insulin infusion till the ketoacidosis was reversed, thereafter responding well to sulphonylureas and at age of 13 months going into complete remission. At age of 11 months developmental delay in the form of negative neck holding and inability to sit without support was seen. The child is 3 years of age now, euglycemic without any insulin or oral hypoglycemic agents but has severe developmental delay. Genetic analysis was negative for mutations of KCNJ11, 6q24, Glucokinase and IPF-1 genes. A mutation R1183W was found in the ABCC8 gene encoding SUR1, which was the cause of neonatal diabetes in this case.

Objective: Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear., Research Design and Methods: Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR., Results: Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells., Conclusions: These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.

Diabetic lipaemia, severe hypertriglyceridaemia associated with diabetic ketoacidosis, is a well recognised, but rare condition. Why this occurs in some patients and not others is unknown. We report a case of extreme lipaemia in a 20-year-old woman with type 1 diabetes who presented to hospital with diabetic ketoacidosis (DKA). At admission the patient's blood was grossly lipaemic and plasma lipid analyses showed triglyceride and cholesterol concentrations of 379 mmol/L and 52 mmol/L, respectively. She had no peripheral stigmata of chronic hyperlipidaemia and 1 year previously her plasma triglyceride and total cholesterol concentrations were 2.5 mmol/L and 4.4 mmol/L respectively. She was treated with insulin and the hypertriglyceridaemia resolved over several days. Because of the marked hypertriglyceridaemia, lipoprotein lipase (LPL) genetic testing was performed. Sequencing of the LPL gene revealed that she was heterozygous for the common S447X LPL variant and heterozygous for a novel missense mutation in exon five (I225N). Ile(225) is highly conserved among species and this mutation is predicted to impair function of the mature LPL protein. We conclude that heterozygosity for LPL mutations may predispose to transient severe hypertriglyceridaemia, when combined with insulin deficiency.

A two-month-old Danish girl was admitted to the hospital in diabetic ketoacidosis and diagnosed with permanent neonatal diabetes mellitus (PNDM). She received continuous insulin treatment until she was genetically tested at the Steno Diabetes Centre. She carried a KCNJ11 Arg201His mutation, an activating mutation in the KCNJ11-gene which encodes the ATP-sensitive potassium subunit Kir6.2 in the beta cell which is responsible for insulin secretion. As recommended in the literature, she was successfully shifted from insulin therapy to sulfonylurea tablets at the age of three years and nine months. PNDM-patients should be screened for gene mutations regardless of current age.

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Objective: Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of beta-cell autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes., Research Design and Methods: A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, beta-cell functional reserve, insulin sensitivity, and insulin requirement. Frequencies of susceptibility and resistance alleles at HLA DQA1, DQB1, and DRB1 loci were correlated with clinical and phenotypic features of KPD subgroups and compared with those of ethnic-specific population control subjects., Results: Susceptibility alleles were more frequent (P < 0.0001) in the two A+ than the two A- KPD subgroups; in the latter, the frequency was no greater than in population control subjects (except for DQB1*0302). Susceptibility alleles differentiated the two clinically similar beta- subgroups (more frequent in A+beta- than A-beta- KPD; P < 0.01). Resistance alleles were more frequent in the two beta+ than the two beta- KPD subgroups (P < 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American A-beta+ KPD patients than in African-American control subjects. DQB1*0302 was more frequent in all KPD subgroups compared with control subjects., Conclusions: HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPD. Inheritance of these alleles may influence long-term beta-cell functional reserve.

Ketoacidotic coma is one of the possible diabetes mellitus first symptoms. It results from complete or relative lack of insuline and is often associated with type 1 diabetes. The authors report a case of a 45-years old woman with inaugural diabetes of which atypical features have motivated the study of MODY gene (maturity-onset diabetes of the young). Gly574ser polymorphism in the HNF-1alpha gene was found, in homozygous state, and the question of the responsibility of this polymorphism in this diabete is asked.

Type 1 diabetes (T1D) comprises all forms of autoimmune-mediated and idiopathic beta-cell destruction leading to absolute insulin deficiency. The etiological heterogeneity of T1D has been recognized for the last decades, but it has been divided into only two subtypes so far: autoimmune (T1D)A and non-autoimmune (T1D)B mediated. Polygenic T1DA (isolated or associated to other autoimmune diseases) is the most prevalent type of T1D. T1DA might be part of rare monogenic syndromes related to mutations in the autoimmune regulator gene (AIRE) and FOXp3. Non-autoimmune forms of T1D correspond to approximately 4 to 7% of newly diagnosed T1D and include T1DB, as well as other types of atypical diabetes, for example fulminant type 1 diabetes and adult ketosis-prone diabetes. A new expression of diabetes in young with insulin resistance and obesity, along with the presence of pancreatic autoimmunity markers, namely auto-antibodies to islet cell antigens, is called double diabetes (DD), T1DA plus type 2 diabetes. Evidence has been collected concerning the potential effect of obesity-linked cytokines in amplifying the autoimmune response in DD. Therefore all these issues are presented and discussed in this review as the concept of heterogeneity of Type 1 Diabetes.